Methods and system for processing dispersible fine powders

ABSTRACT

The invention provides an agglomerate composition composed of units of aggregated fine particles and methods for its manufacture and use. The agglomerate composition units are composed of fine particles having a mean particle size in the range of 1 μm to 5 μm, and usually includes a medicament powder. The agglomerate units have a mean size in the range from 200 μm to 500 μm and have a friability index in the range from about 10 to 60.

This application is a division of Ser. No. 08/853,618, filed May 9, 1997now U.S. Pat. No. 5,922,354 which is a division of Ser. No. 08/483,467filed Jun. 7, 1996 now U.S. Pat. No. 5,654,007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to a system and methods forprocessing fine dispensable powders. More particularly, the presentinvention relates to a system and methods for forming fine powderedmedicaments into agglomerates for easier processing, where theagglomerates are readily broken back down to the fine powder when neededfor pulmonary delivery or other uses benefitting from fine powders.

Effective delivery to a patient is a critical aspect of any successfuldrug therapy. Various routes of delivery exist, and each has its ownadvantages and disadvantages. Oral drug delivery of tablets, capsules,elixirs, and the like, is perhaps the most convenient method, but manydrugs are degraded in the digestive tract before they can be absorbed.Such degradation is a particular problem with modern protein drugs whichare rapidly degraded by proteolytic enzymes in the digestive tract.Subcutaneous injection is frequently an effective route for systemicdrug delivery, including the delivery of proteins, but enjoys a lowpatient acceptance. Since the need to inject drugs on a frequentschedule, such as insulin one or more times a day, can be a source ofpoor patient compliance, a variety of alternative routes ofadministration have been developed, including transdermal, intranasal,intrarectal, intravaginal, and pulmonary delivery.

Of particular interest to the present invention are pulmonary drugdelivery procedures which rely on inhalation of a drug dispersion oraerosol by the patient so that the active drug within the dispersion canreach the distal (alveolar) regions of the lung. It has been found thatcertain drugs are readily absorbed through the alveolar region directlyinto blood circulation. Pulmonary delivery is particularly promising forthe delivery of proteins and polypeptides which are difficult to deliverby other routes of administration. Such pulmonary delivery can beeffective both for systemic delivery and for localized delivery to treatdiseases of the lungs.

Pulmonary drug delivery (including both systemic and local) can itselfbe achieved by different approaches, including liquid nebulizers,metered dose inhalers (MDI's) and dry powder dispersion devices. Drypowder dispersion devices are particularly promising for deliveringprotein and polypeptide drugs which may be readily formulated as drypowders. Many otherwise labile proteins and polypeptides may be stablystored as lyophilized or spray-dried powders by themselves or incombination with suitable powder carriers.

The ability to deliver proteins and polypeptides as dry powders,however, is problematic in certain respects. The dosage of many proteinand polypeptide drugs is often critical so it is necessary that any drypowder delivery system be able to accurately, and precisely (repeatably)deliver the intended amount of drug. Moreover, many proteins andpolypeptides are quite expensive, typically being many times more costlythan conventional drugs on a per-dose basis. Thus, the ability toefficiently deliver the dry powders to the target region of the lungwith a minimal loss of drug is critical.

An exemplary dry powder dispersion device for efficiently delivering drypowder medicaments to the lungs is described in copending U.S. PatentApplication Ser. No. 08/309,691, filed Sep. 21, 1994 and now U.S. Pat.No 5,785,049, the disclosure of which is herein incorporated byreference. Such a dispersion device is constructed to receive thepowdered medicament in a receptacle having a puncturable lid or otheraccess surface: The receptacle is placed in the device, and a feed tubeis penetrated into the lid of the receptacle to provide access to thepowdered medicament therein. A high velocity gas stream is then flowedpast a portion of the tube, such as an outlet end, to draw powder fromthe receptacle, through the tube, and into the flowing gas stream toform an aerosol for inhalation by the patient.

Of particular interest to the present invention are the physicalcharacteristics of the fine powders to be delivered by such apparatus,and particularly, the flowability of the fine powders. Most fine powdershave poor flowability which can often be problematic when attempting toprocess, e.g. move and meter, the powders. For example, in the case offine powder medicaments, poor flowability increases the time and/orreduces the accuracy of filling the receptacles with unit doses of thepowdered medicaments for subsequent use in a powder inhaler. Therefore,a significant improvement in the powder flow will increase theprobability for success of filling processes.

To improve the flowability of fine powder medicaments, some haveproposed the use of a blending process where the powdered medicamentsare combined or blended with larger carrier particles, such as coarse(i.e greater than 25 μm) lactose particles, which have easier handlingand flowability characteristics. Use of a carrier, however, presents avariety of problems including dilution of the drug, requiring a largerdispersion volume for a given drug dosage, and the potential for poorcontent uniformity of the blend.

Another proposed process for improving flowability is to increase thesize of small particles by agglomeration where the fine powders arecombined into larger-sized aggregated units. Such aggregated units canbe formed by a variety of processes including low shear granulation,high shear granulation, roller compaction or dry granulation, andextrusion. One particular concern with the formulation of inhalationpowders into aggregated units is the resulting friability of theaggregated units, i.e. the ability of the aggregated units to be brokendown to the fine powder. If the aggregated units are not sufficientlyfriable, they cannot be sufficiently broken down by an inhaler when usedfor pulmonary delivery. Another concern with the formulation ofinhalation powders into aggregated units is their resulting size. Theaggregated units should have a narrow size distribution so that they maybe utilized in existing inhalation devices. For example, if theaggregated units are too large, they can become trapped within theholding receptacle and will not be delivered to the lungs.

The extrusion process is advantageous over other agglomeration processesin that it allows for the rapid formation of aggregated units in aspecific size range using low pressures. In the extrusion process, thefine powder is wetted with a liquid, referred to as a binding liquid,and then forced through a screen to form an extrudate. The extrudate isthen dried and sieved to break up the extrudate into the aggregatedunits. Typically, water, ethanol, glycerin, iso-propanol, or methanolare used as the binding liquid. One particular drawback to the use ofsuch liquids is that a significant portion of proteins are susceptibleto denaturation following exposure to alkanols. Alkanols and water canalso solubilize excipients in the powder, such as carbohydrates andbuffer salts. Excipients solubilized by the binding liquid can lead tothe formation of strong crystalline bridges between particles, therebystrengthening the aggregated units and making them more difficult todisperse.

Hence, for these and other reasons, it would be desirable to provideimproved systems and methods for agglomerating fine powders intoaggregated units that would overcome or greatly reduce such problems.The systems and methods should allow for the aggregated units to beproduced with a narrow size distribution and to have an appropriatelevel of friability, i.e. neither too high nor too low, so that theaggregated units can be used with existing dry power inhalers whichrequire the break up of the aggregated units prior to inhalation. In oneaspect, it would further be desirable to provide systems and methods forproducing agglomerate powders with a binding liquid that does notinteract with the hydrophilic or lipophilic components of the powder.

2. Description of the Background Art

Dry powder dispersion devices for medicaments are described in a varietyof patent documents, including U.S. Pat. Nos. 4,137,914; 4,174,712;4,524,769; 4,667,688; U.K. Patent Application No. 2,156,738; EuropeanPatent Application No. 87850060.2; and PCT Application Nos.PCT/SE93/00389; PCT/SE93/01053; and PCT/DK90/00005.

A process for providing water-soluble micronized substances is describedin European Patent Application No. 92850062.8.

A system for administration of liposomes to mammals is described inEuropean Patent Application No. 87850273.1.

U.S. Pat. No. 5,376,359 describes a method for making a stabilizedaerosol drug formulation.

British Patent No. 1,151,017 describes a process for producing finelydivided metal powders.

A variety of publications describe various powder inhalers including S.P. Newman et al., Deposition and clinical efficacy of turbutalinesulphate from Turbuhaler, a new multi-dose powder inhaler, Eur Respir J,1989, 2:247-252; S. Pedersen, How to use a Rotahaler, Arch Dis Child,1986, 61:11-14.

Dr. Gabrie M. H. Meesters, Not so dusty, describes market demand forfree flowing powders through agglomeration.

Product brochures Fine-granulation technology, LCI Corporation,Processing Division, Charlotte, N.C. and Agglomeration: sizing up theagglomeration process, BEPEX Corporation, Minneapolis, Minn., ©1992,describe processes for producing agglomerated particles.

E. M. Phillips et al., Formulation Development of Spray Dried Powdersfor Inhalation (Abstract), Pharm. Res., 11(10), S-158, 1995 describesthe aerosolization of spray dried powders.

SUMMARY OF THE INVENTION

The invention provides an agglomerate composition composed of aggregatedunits of fine particles along with methods for its manufacture and use.By the term "aggregated unit", it is meant that a number of fineparticles are bound together into a single geometric configuration. Aplurality of such units are referred to as aggregated units. Theaggregated units are unconnected to each other and collectively form theagglomerate composition. The aggregated units will usually have a meansize in the range from 50 μm to 600 μm, preferably between about 150 μmand 500 μm, and more preferably between 200 μm to 500 μm, and arecomposed of fine particles having a mean particle size in the range from1 pm to 5 μm. Forming the fine particles into aggregated units in thismanner improves the flowability of the fine particles, thereby allowingfor easier processing and handling of the particles. The agglomeratecomposition is formed in such a way that the aggregated units have afriability index (as described hereinafter) in the range from about 10to 60. Preferably, the particles comprise a medicament powder useful inpulmonary drug delivery procedures where the medicament powder isinhaled by a patient so that the active drug in the powder can reach thedistal regions of the lung. Preferable medicament powders include thosehaving medicaments such as proteins, nucleic acids, carbohydrates,buffer salts, peptides, other biomolecules, small molecule drugs, andthe like. By forming the medicament powder into an agglomeratecomposition, the medicament can more easily be moved and metered priorto inhalation while also having the ability to easily be broken down tothe fine particles when needed for delivery to the patient's lungs.

In one aspect of the invention, an agglomerate composition is providedwhich is composed of fine particles formed into aggregated units, withthe fine particles having a mean particle size in the range from 1 μm to5 μm. The aggregated units have a mean size in the range from 200 μm to500 μm and are formed by employing a nonaqueous solvent binding liquid.The use of a nonaqueous solvent is desirable in that the carbohydratesand proteins of the medicament powders are typically poorly soluble insuch a solvent. Poor solubility is desirable so that the formation ofcrystalline bridges between particles will be minimized. Theminimization of crystalline bridges will allow the aggregated units tobe broken down into the fine powder when needed. Many nonaqueoussolvents also have a low boiling point, and therefore a high vaporpressure, so that they may be readily removed from the aggregated units.Additionally, most nonaqueous solvents have a low surface tension andtherefore form weak bonds between particles, allowing the agglomeratedunits to be broken down into the fine particles when needed. Further,some nonaqueous solvents will not denature proteins. Preferablenonaqueous solvents include, but are not limited to toluene, xylene,benzene, acetone, hexane, octane, chloroform, methylene chloride, andfluorocarbons.

Use of a fluorocarbon liquid in forming the aggregated units isparticularly preferable because the fluorocarbon liquid will notdissolve lipophilic and hydrophilic compounds. Further, the fluorocarbonliquid has a low surface tension which forms a relatively weak bondbetween the fine particles of the aggregated units so that theaggregated units can easily be broken down to the fine particles whenneeded. Fluorocarbon liquids further have a high vapor pressure and aretherefore easy to remove from the particles during formation of theaggregated units. Fluorocarbon liquids are also biocompatible with manypharmaceutical formulations. Preferable fluorocarbon liquids include butare not limited to perfluorodecalin and perfluorooctyl bromide.

In another aspect of the invention, a receptacle is provided having asealed internal volume and a penetrable wall portion. Within the sealedinternal volume is an amount of an agglomerate composition as previouslydescribed. The amount of agglomerate composition is preferably a unitdosage of a medicament. When filled with the agglomerate medicament, thereceptacle is useful in an inhalation device using a gas stream towithdraw the agglomerate composition from the receptacle where theaggregate units are broken down to the fine particles for delivery tothe patient's lungs.

According to one method of the invention, such a receptacle is providedwith a fine powder agglomerate composition where the fine powder ischaracterized by a mean particle size in the range from 1 μm to 5 μm.The fine powder is formed into aggregated units having a mean size inthe range from 50 μm to 600 μm, preferably between about 150 μm and 500μm, and most preferably between 200 μm to 500 μm. The agglomeratecomposition from the receptacle is extracted in a gas stream fordelivery to a patient's lungs, with the gas stream having sufficientdisruptive force to break down the aggregated units substantiallycompletely, i.e., at least 30%, preferably at least 50%, and mostpreferably at least 70%, to the fine particles. In one particularaspect, the agglomerate composition is extracted by flowing the gasstream past a tube inserted into the receptacle.

In one aspect, the gas stream is flowed at a sonic velocity to providesufficient disruptive force. In another aspect, usually at least 55percent by weight, preferably at least 70 percent by weight, and morepreferably at least 90 percent by weight of the agglomerate compositioninitially present in the receptacle is extracted into the airstream fordelivery to the patient's lungs.

The invention provides a method for agglomerating fine particles.According to the method, a powder of fine particles is combined with abinding liquid to produce a wetted mass, such as a granulation or apaste. The wetted mass is then divided into small volumes which aredried to remove the binding liquid and to produce dry powder agglomerateunits having a first size distribution. The dry powder agglomerate unitsare then adjusted to have a second size distribution characterized by afriability index in the range from about 10 to 60.

The fine particles preferably have a mean particle size in the rangefrom 1 μm to 5 μm. When adjusted to the second size distribution, thedry powder agglomerate units preferably have a mean size in the rangefrom 50 μm to 600 μm, preferably between about 150 μm and 500 μm, andmost preferably between 200 μm to 500 μm. The aggregated units will beformed such that substantially all, i.e. about 90% or more, fall withina narrow size distribution, i.e. within about ±250 μm, more preferablywithin about ±150 μm, and most preferably within about ±100 μm.

In an exemplary aspect, the paste or granulation is divided into smallvolumes by extruding the paste or granulation through a screen havingholes in the range from 40 μm to 650 μm, and more preferably in therange from 150 μm to 500 μm. Preferably, the holes are circular ingeometry, thereby producing elongate cylindrical portions of extrudate.The extrudate is preferably dried at a temperature in the range from 15°C. to 40° C. Preferable environments for drying the extrudate includethe use of forced convection with dry air or by placing the extrudate ina vacuum. To adjust the agglomerate units to the second sizedistribution, the dry powder agglomerate units are preferably sieved.Optionally, the dry powder agglomerate units can further be adjusted tohave a spherical geometry, often referred to as spheronization. In oneaspect, the agglomerate units are spheronized by rolling the agglomerateunits in a container.

In another exemplary aspect, the binding liquid is preferably anonaqueous solvent, more preferably a fluorocarbon, and the fineparticles will preferably comprise a medicament powder. The amount ofbinding liquid added to the medicament powder is preferably based on thesurface area of the powder. Preferably, the fluorocarbon liquid isperfluorodecalin, and the fine particles have a mean particle size inthe range from 1 μm to 5 μm. With such a configuration, the amount offluorocarbon added is preferably in the range from 0.5 gram to 5 gramper gram of fine particles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is flow chart illustrating an exemplary method for agglomeratingfine particles according to the present invention.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The invention provides an agglomerate composition composed of aggregatedfine particle units, along with methods for its manufacture and use.Although useful in a wide variety of applications, the agglomeratecomposition will find its greatest use with pulmonary drug deliveryprocedures which rely on the inhalation of a drug dispersion by apatient so that the active drug within the dispersion can reach thealveolar regions of the lung.

The agglomerate composition is provided to improve the ability to handleand process the fine particles. By bonding the fine particles togetherto form aggregated units, flowability of the particles is improved.Improved flowability is desirable in that it allows for easier transferand metering of the particles. The aggregated units are formed bybinding the fine particles together with a bond sufficiently strong tohold the fine particles together during handling and processing yet weakenough so that the aggregated units can be broken down to the fineparticles when needed, usually upon dispersion into an aerosol fordelivery of the particles to the lungs.

The fine particles employed in the present invention have a size that issmall enough to effectively be delivered to the alveolar regions of thelung when inhaled by a patient. Such particles are very fine, usuallyhaving a mean size in the range from 1 μm to 5 μm. Such small sizes makehandling and metering of the particles difficult. For instance, transferof the particles often occurs through a funnel. When traveling throughthe funnel, the particles often clump together and clog the funnel. Byforming the particles into agglomerates, flowability is improvedallowing for easier movement of the particles.

In a preferred aspect of the invention, the articles comprise amedicament powder. Exemplary medicament powders include powders made ofproteins, nucleic acids, peptides, buffer salts, other biomolecules, andthe like, and can include carrier materials such as carbohydrates. Oneparticularly preferable medicament powder is insulin which has beenshown to be effective when delivered in powdered form.

Aggregated units of the invention preferably have a mean size in therange from 50 μm to 600 μm, more preferably between about 150 μm and 500μm, and most preferably between 200 μm to 500 μm. Such a size allows forimproved handling and flowability of the powder. As described in greaterdetail hereinafter, such a size is also small enough for the aggregatedunits to be effective when used in inhalation devices. To furtherimprove the flowability, the aggregated units can optionally be providedwith a spherical geometry. When forming the aggregated units, it isdesirable to have substantially all, i.e. about 90% or more, fall withina narrow size distribution, i.e. within about ±250 μm, more preferablywithin about ±150 μm, and most preferably within about ±100 μm. Such anarrow size distribution makes it easier for the aggregated units to bedispersed within an inhaler.

To bind the fine particles into aggregated units, a binding liquid isemployed. The binding liquid is added to the particles, with the surfacetension of the liquid holding the particles together. When wetted, agranulation or paste is formed allowing the particles to be formed ormolded into an aggregated unit having the desired shape and size. Theaggregated unit is then dried to remove the binding liquid and to leavethe aggregated unit in the desired shape.

The resulting aggregated unit is held together by a series of bonds thatare strong enough to hold the aggregated unit together during normalhandling and metering procedures. At the same time, the bonds are weakenough so that the aggregated unit can be broken down to the fineparticles when needed, i.e., the aggregated units have an appropriatelevel of friability. Sufficient friability is particularly important ininhalation devices where it is desirable to have the aggregated unitsbroken down to the fine particles when delivered to the lungs. As usedherein, the friability of the aggregated units is determined by thefollowing friability test. The friability test measures the attrition ofthe aggregated units after shaking the units through a stack of sieves,using a specific frequency and amplitude, for a specified time.

The sieve stack includes seven vertically arranged screens. Each screenis 3 inches in diameter and is separated from an adjacent screen by 1.25inches. In order from top to bottom, the screen sizes are: 1000 μm, 500μm, 425 μm, 355 μm, 300 μm, 250 μm, and 150 μm. Below the 150 μm screenis a collection pan. To test the friability, an amount of the aggregatedunits in the range from about 0.4 g to 0.5 g is weighed to give abeginning weight W₁. The weighed aggregated units are then placed on the1000 μm screen, and the entire stack is vibrated for 20 minutes with anamplitude of approximately 1 cm and at a frequency of approximately 5Hz. After the 20 minutes, the vibration is ceased, and the aggregatedunits which have not been broken down to the fine particles arecollected and weighed to give a weight W₂. The aggregated units caneasily be collected by pouring them from the sieve stack since the finepowder will have either been collected in the pan or will coat thescreens. The ending weight W₂ is then divided by the beginning weight W₁to give a percentage of aggregated units that have not been broken downto the fine particles. The particular numerical values of thepercentages are referred to as the friability index. For example, if 50percent of the aggregated units were broken down using the friabilitytest, the friability index for such aggregated units would be 50. Apreferable friability index for pulmonary powder inhalers as describedherein is in the range from about 10 to 60.

In addition to holding the agglomerate together, the binding liquid alsoreduces the level of dust, or loss of product, when applied to thepowder. In this way, waste of the powdered medicaments is reduced.

Exemplary binding liquids include nonaqueous solvents, preferablyfluorocarbon liquid, and more preferably perfluorodecalin orperfluorooctyl bromide, with the most preferred being perfluorodecalin.Other exemplary nonaqueous solvents include toluene, xylene, benzene,acetone, hexane, octane, chloroform, and methylene chloride. The use ofa nonaqueous solvent is desirable in that carbohydrates and proteins areusually poorly soluble in them, thereby minimizing the formation ofcrystalline bridges between particles. Further, most nonaqueous solventshave a low surface tension which allows the agglomerates to more easilybe broken down to the fine particles when needed. Moreover, manynonaqueous solvents have a low boiling point, and hence high vaporpressure, allowing them to be easily removed from the agglomerates. In afurther aspect, some nonaqueous solvents will not denature proteins.

The use of fluorocarbon liquids are particularly preferable in that theyare hydrophobic and do not dissolve carbohydrates or proteins.Fluorocarbon liquids are also lipophobic and do not interact with theproteins. Further, fluorocarbon liquids have a low surface tension andtherefore form weak bonds between the particles so that the desiredlevel of friability for the agglomerates can be obtained. Fluorocarbonliquids also have a high vapor pressure and are therefore easy to removefrom the agglomerates. In a further advantage, fluorocarbon liquids donot contain fluorine and are therefore ozone-friendly. In a furtheraspect, fluorocarbon liquids are biocompatible with most pharmaceuticalformulations, such as blood substitutes and imaging aids. Suitablefluorocarbon liquids are commercially available from a variety ofcommercial suppliers including PCR, Inc. (Gainesville, Fla.), SigmaChemical Company (St. Louis, Mo.), and Aldrich Chemical company, Inc.(Milwaukee, Wis).

Delivery of powdered medicaments to the lungs is usually accomplished byuse of an inhalation device which fluidizes the powdered medicament inan airstream which can then be inhaled by the patient to deliver themedicament to the patient's lungs. Hence, before pulmonary delivery, theaggregated units must be broken down to the powdered medicament. Byproviding the aggregated units with the desired friability, theaggregated units can be broken down into powdered form within theinhaler. In this way, the powdered medicaments can remain in agglomerateform for measurement and handling until needed for pulmonary delivery bythe inhaler.

The aggregated units are usually delivered to the inhaler in unit dosagereceptacles, commonly referred to as blister packs or cartridges. Themanufacture of blister packs is well-known in the pharmaceuticalpackaging art and need not be described further. To extract theaggregated units from the receptacle, a wall of the receptacle ispierced when the receptacle is held within the inhaler. An exemplaryinhaler is described in U.S. Patent Application Ser. No. 08/309,691,filed Sep. 21, 1994 now U.S. Pat. No. 5,785,049, the disclosure of whichhas previously been incorporated herein by reference. With thereceptacle opened, the aggregated units are extracted into a gas streamhaving sufficient disruptive force to break down the aggregated units tothe fine particles. When having the desired friability, the aggregatedunits can be broken down to the fine particles when the gas stream isflowed at a velocity sufficient to provide adequate shear forces neededto break down the aggregated units. Preferably, such a gas stream isflowed at a sonic velocity to provide the sufficient disruptive force.Optionally, when the aggregated units are placed into the blister packs,the blister packs can be subjected to vibratory energy. Subjecting theaggregated units to vibratory energy when within the blister packsassists in breaking down the aggregated units to the fine particlesbefore they are extracted by the inhaler. In this way, the aggregatedunits can be produced with a smaller friability index and still beuseful in pulmonary delivery procedures.

The aggregated units should be broken down substantially completely,i.e., at least 30%, preferably at least 50%, and most preferably atleast 70% of the aggregated units that are extracted from the receptaclebeing broken down to 1 μm to 5 μm, before being inhaled by the patient.Such decomposition to the fine particles is realizable when theaggregated units have a friability index in the range from about 10 to60. When having the desired mean size range of 200 μm to 500 μm,substantial complete removal of the aggregated units (usually at least55 percent, and preferably at least 70 percent, and more preferably atleast 90 percent by weight) from the interior of the receptacle isobtainable. Formation of aggregated units having a mean size range ofgreater than about 600 μm reduces the percentage of powder removed fromthe receptacle by the airstream because the larger aggregated units tendto become trapped behind the penetrated walls of the receptacle.

Referring to FIG. 1, an exemplary method for agglomerating fineparticles will be described. According to the method, a binding liquidis added to a powder of fine particles to produce a wetted powder mass.Preferably, the fine particles are a medicament powder having a meanparticle size in the range from 1 μm to 5 μm, and the binding liquid isa nonaqueous solvent, preferably fluorocarbon, and more preferablyperfluorodecalin. The granulation or paste is mixed to ensure uniformdistribution of the binding liquid. After mixing, the granulation orpaste is extruded to divide the granulation or paste into smallervolumes. The granulation or paste is preferably extruded by pressing thegranulation or paste through a screen having holes in the range from 40μm to 650 μm, preferably at about 150 μm to 500 μm, and more preferablyat about 250 μm to 400 μm. Extrusion screens having less than 500 μmholes can be provided by mechanical punching, electrical discharge, orlaser drilling a thin sheet of metal as is known in the art. The holesin the extrusion screen are preferably circular in geometry so thatelongate cylindrical portions of extrudate are formed when the paste ispressed through the screen.

The extrudate is then dried to remove the binding liquid from theextrudate. Drying can be accomplished in a variety of ways includingplacing the extrudate in a vacuum chamber having a vacuum in the rangefrom 250 mmHg to 650 mmHg, and with a temperature within the chamberbeing in the range from 15° C. to 40° C. or by forced convection withdry air having a temperature in the range from about 15° C. to 40° C.After drying, the extrudate is sieved to break up the extrudate intoagglomerated particle units and to classify the agglomerated particleunits by size. Preferably, the sieve will have holes sized in the rangefrom 150 μm to 1000 μm and will be vibrated either at a frequency in therange from 0.5 Hz to 10 Hz and at an amplitude in the range from about 5mm to 50 mm or, alternatively, vibration may be accomplished by atapping action combined with lateral and/or tiling motions or circularrotation.

The resulting agglomerated particle units preferably have a mean size inthe range from 50 μm to 600 μm, more preferably between about 150 μm and500 μm, and most preferably between 200 μm to 500 μm. If needed, theagglomerated particle units can be subjected to a spheronization processto spheronize the agglomerated units. Spheronization is often desirablebecause it can improve the flowability of the agglomerated particleunits. Spheronization can occur by rolling the agglomerated particleunits, such as in a metal or a glass container.

The amount of binding liquid added to the medicament powder is generallybased on the surface area of the fine particles, as illustrated in thefollowing examples. When using fluorocarbon liquid as the binding agentalong with fine particles having a mean particle size in the range from1 μm to 5 μm, the amount of fluorocarbon added is preferably in therange from 0.5 gram to 5 gram per gram of fine particles.

The present invention is explained in greater detail in the followingnon-limiting examples.

EXAMPLES

Fine powders having a weight of about 0.5 g to 10 g were combined with anonaqueous solvent to form a wetted mass. The wetted mass was thenextruded through a screen. The resulting extrudate was then dried (byforced convection or in a vacuum) at room temperature for at least onehour to remove the nonaqueous solvent. The dried extrudate was thensieved to produce aggregated units. The size of the aggregated units wasmeasured to determine the percentage falling between 200 μm and 500 μm.The friability of the first three batches of aggregate units was alsomeasured according to the friability test as previously described. Theresults were acceptable if the aggregated units had a friability indexbetween 10 and 60. The friability of the rest of the batches' aggregatedunits was acceptable if the aggregated units could be utilized in thedevice described in U.S. patent application Ser. No. 08/309,691 now U.S.Pat. No. 5,785,049 which has previously been incorporated by reference.The results of six different fine powder compositions are shown in Table1 below.

                                      TABLE 1                                     __________________________________________________________________________    Fine      Nonaqueous Solvent/  Extruded Material in                           Powder Composition                                                                      Amount Added (g/g)                                                                       Screen Type/Hole Size                                                                   the Proper Size Range                                                                   Friability                           __________________________________________________________________________    Mannitol with HSA                                                                       PFOB/2.0   Standard Sieve Screen/                                                                  92%       Acceptable                                                355 μm                                                Mannitol with Insulin                                                                   PFD/3.8    Laser Drilled/250 μm                                                                 69%       Acceptable                           Mannitol with HSA                                                                       PFD/2.2    Laser Drilled/175 μm                                                                 73%       Acceptable                           Mannitol with HSA                                                                       Acetone/0.8                                                                              Laser Drilled/355 μm                                                                 12%       Acceptable                           Mannitol with HSA                                                                       Methylene Chloride/1.3                                                                   Laser Drilled/355 μm                                                                 14%       Acceptable                           Mannitol with HSA                                                                       Toluene/0.9                                                                              Laser Drilled/355 μm                                                                 64%       Acceptable                           __________________________________________________________________________

Although the foregoing invention has been described in some detail byway of illustration and example, for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

What is claimed is:
 1. A method for dispersing fine particles in aflowing gas stream, said method comprising:providing a receptaclecontaining a fine powder agglomerate composition, wherein the powder hasa mean particle size in the range from 1 μm to 5 μm and the agglomeratecomposition comprises aggregated units having a size in the range from50 μm to 600 μm; and extracting the agglomerate composition from thereceptacle in a gas stream having sufficient disruptive force to breakdown the units substantially completely to the fine particles.
 2. Amethod as in claim 1, wherein the gas stream is flowed at a sonicvelocity to provide the sufficient disruptive force.
 3. A method as inclaim 1, wherein at least 55% by weight of the amount of aggregatecomposition initially present in the receptacle is extracted into theair stream.
 4. A method as in claim wherein the extracting step furthercomprises flowing the gas stream past a tube inserted into thereceptacle.